The present invention relates to a process for preparing 1-substituted 5- and/or 3-hydroxypyrazoles of the formulae I and II, respectively 
in which R1 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl or C1-C4-alkoxy, where these groups may be substituted by halogen, C1-C4-alkoxy, phenoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or by a cyclic ring system having 3-14 ring atoms, which comprises [lacuna]
1-Substituted 5- and 3-hydroxypyrazoles are used as intermediates for preparing pharmaceutics and crop protection agents, in particular herbicides, and are disclosed, for example, in WO96/26206, WO 97/23135, WO 97/19087, U.S. Pat. No. 5,631,210, WO 97/12885, WO 97/08164, ZA 9510980, WO 97/01550, WO 96/31507, WO 96/30368, WO 96/25412 and U.S. Pat. No. 5,663,365.
Processes for their preparation are therefore of interest.
To date, the following syntheses are known as processes for preparing lower 1-alkyl-5-hydroxypyrazoles:
1. a preparation where 2-methyl-1-(p-toluenesulfonyl)-3-pyrazolidone or 2-methyl-1-1-acetyl-pyrazolidone [sic] is hydrolyzed (J. Prakt. Chem. 313 (1971), 115-128 and J. Prakt. Chem. 313 (1971), 1118-1124).
2. a variant in which alkyl 5-hydroxy-1-alkylpyrazole-4-carboxylate is synthesized by cyclization of a dialkyl alkoxymethylenemalonate with lower alkylhydrazines, an aqueous solution of mineral acid is subsequently added to this reaction product and hydrolysis and decarboxylation are carried out simultaneously (see JP 61257974, JP 60051175, JP 58174369, JP 58140073 and JP 58140074 and also U.S. Pat. No. 4,643,757).
3. a synthesis in which ethyl propiolate is reacted with methylhydrazine to give 5-hydroxy-1-methylpyrazole (Annalen 686 (1965), 134-144).
4. a synthesis route in which 3-hydrazinopropionic esters, which are formed by addition of hydrazine to acrylic esters, are reacted with aldehydes to give the corresponding hydrazones, which are subsequently cyclized (see JP 06166666, JP 61229852 and JP 61268659 and also EP 240001).
5. a synthesis variant in which a 5-hydroxy-1-methylpyrazole-3-carboxylic acid is cleaved thermally (Chem. Ber. 109 (1976), 261).
6. a process in which 3-alkoxyacrylic esters are reacted with methylhydrazine and ethylhydrazine to give 1-methyl-5-hydroxypyrazole and 1-ethyl-5-hydroxypyrazole, respectively (see JP 189 271/86, EP-A-837 058).
7. a process in which 2-haloacrylic esters are reacted with hydrazine derivatives to give 1-substituted 3-hydroxypyrazoles (see U.S. Pat. No. 5,663,365).
The process of the 1st synthesis route mentioned above entails several steps and is complicated. Introduction and removal of a protecting group is awkward, means an additional number of steps and reduces the yield.
The 2nd preparation possibility entails several steps; moreover, in addition to the 1-alkyl-5-hydroxypyrazoles, the regioisomers of the target compound are formed at the same time, and they have to be separated off from the target compounds in a complicated procedure. Furthermore, the synthesis is associated with a poor C yield since a C4 building block is employed from which, at the end of the process, a carbon atom has to be cleaved off again.
In the 3rd synthesis variant, which describes only the preparation of 1-methyl-5-hydroxypyrazole, it is unavoidable to employ highly hyperstoichiometric amounts of methylhydrazine, thus rendering the process uneconomical. In addition, the isomer 3-hydroxy-1-methylpyrazole, which is also formed, has to be separated off from 1-methyl-5-hydroxypyrazole in a complicated procedure during purification. Furthermore, owing to the high cost of propiolic ester, this process is uneconomical.
The process of the 4th alternative entails several steps and is complicated. The last step of the complex process affords only poor yields and a large number of byproducts.
The thermal cleavage of the 5th synthesis route requires a high temperature, and the yield of 6% is very low.
The 6th synthesis route, which describes only the preparation of 1-methyl-5-hydroxypyrazole, uses 3-alkoxyacrylic esters which are difficult to prepare and are expensive. The preparation of 3-alkoxyacrylic esters is carried out by reaction of methanol with expensive propiolic esters (Tetrahedron Lett. 24 (1983), 5209, J. Org. Chem. 45 (1980), 48, Chem. Ber. 99 (1966), 450, Chem. Lett. 9 (1996), 727-728), by reacting xcex1,xcex1-dichlorodiethyl ether, which is expensive and difficult to synthesize, with bromoacetic esters (Zh. Org. Khim. 22 (1986), 738), by reaction of bromoacetic esters with trialkyl formates (Bull. Soc. Chim. France N 1-2 (1983), 41-45) and by elimination of methanol from 3,3-dialkoxypropionic esters (DE 3701113) (obtainable by reacting the expensive methyl propiolate with methanol (J. Org. Chem. 41 (1976), 3765)), by reacting 3-N-acetyl-N-alkyl-3-methoxypropionic esters with methanol (J. Org. Chem. 50 (1985), 4157-4160, JP 60-156643), by reacting acrylic esters with alkylamines and acetic anhydride (J. Org. Chem. 50 (1985), 4157-4160), by reacting ketene with trialkyl orthoformate (DK 158462), by palladium- and simultaneously copper-catalyzed reaction of acrylic esters with methanol (DE 4100178.8), by reaction of trichloroacetyl chloride with vinyl ethyl ether (Synthesis 4 (1988), 274), by reacting xcex1,xcex1,xcex1-trichloro-xcex2-methoxybutene-2-one with methanol (Synthesis 4 (1988), 274) and by reacting the sodium salts of 3-hydroxyacrylic esters with alcohols (DB 3641605). The fact that the 3-alkoxyacrylic esters are difficult to obtain thus renders the synthesis according to 6 uneconomical. Moreover, JP 189 271/86 only describes the isolation of the 5-hydroxy-1-methylpyrazole as the hydrochloride, but no details are given for the isolation and purification of the free base. Efforts to apply the reaction conditions described in JP 189 271/86 and to isolate the free base result in only very poor yields which are uneconomical for a preparation of hydroxypyrazoles on an industrial scale.
The 7th synthesis route has the disadvantage that only 3-hydroxypyrazoles can be prepared, and no 5-hydroxypyrazoles. Consequently, these synthesis routes are not satisfactory as economical and efficient processes for preparing 1-substituted 5- and 3-hydroxypyrazoles.
Furthermore, there is no process known from the prior art which permits preparation of both the 1-substituted 5- and the 3-hydroxypyrazole by simple variation of the process parameters.
Moreover, there is no process known from the prior art which leads to the desired 1-substituted 5- and 3-hydroxypyrazoles from simple starting materials such as an alkyl vinyl ether.
It is an object of the present invention to provide a process which allows the preparation of 1-substituted 5-hydroxypyrazoles and/or 3-hydroxypyrazoles in [sic] by changing the process parameters.
It is another object of the present invention to provide a process for preparing 1-substituted 5-hydroxypyrazoles and/or 3-hydroxypyrazoles from easily obtainable starting materials which does not have the abovementioned disadvantages of the prior art processes.
We have found that this object is achieved by the process according to the invention for preparing 1-substituted 5- and/or 3-hydroxypyrazoles of the formulae I and II 
in which R1 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C1-C4-alkoxy or phenoxy, where these groups may be substituted by halogen, C1-C4-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or by a cyclic ring system having 3-14 ring atoms, by reacting
an alkyl 3-alkoxyacrylate of the formula III 
in which R2, R3 independently of one another are C1-C6-alkyl or C3-C6-cycloalkyl with a hydrazine of the formula IV 
in which R1 is as defined above
a) at a pH of 6-11 to give 5-hydroxypyrazoles of the formula I or
b) at a pH of 11-14 to give 3-hydroxypyrazoles of the formula II.
Moreover, we have found a process starting from easily obtainable alkyl vinyl ethers for preparing the alkyl 3-alkoxyacrylate of the formula III by reacting
c) an alkyl vinyl ether of the formula V 
xe2x80x83in which R2 is as defined in claim 1 with phosgene VIa, xe2x80x9cdiphosgenexe2x80x9d VIb or xe2x80x9ctriphosgenexe2x80x9d VIc 
to give an acyl chloride of the formula VII 
d) converting this by elimination of hydrogen chloride into the corresponding 3-alkoxyacryloyl chloride of the formula VIII 
xe2x80x83and
e) esterifying this with an alcohol of the formula IX 
xe2x80x83in which R3 is as defined in claim 1 to give the corresponding alkyl 3-alkoxyacrylate of the formula III.
Surprising and novel in the process according to the invention are the facts that 5- or 3-hydroxypyrazoles of the formulae I and II, respectively, can be prepared selectively by appropriate choice of the reaction conditions, and that easily obtainable starting materials can be employed.
Preferred embodiments of the process according to the invention are shown in the subclaims and in the description below.
Step a):
The reaction of the alkyl 3-alkoxyacrylates of the formula III with hydrazines of the formula IV to give the 1-substituted 5-hydroxypyrazoles is generally carried out by initially charging one of the two reaction participants in a suitable solvent and metering in the second reaction participant at from xe2x88x9230xc2x0 C. to 100xc2x0 C. By addition of a base, the pH is kept at 7-11, preferably 8-11, particularly preferably 9-11. Suitable bases are, for example, alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide and potassium hydroxide, and also tertiary amines.
Preferred bases are alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide and potassium hydroxide. The molar ratio of alkyl 3-alkoxyacrylate III to hydrazine IV is from 1:1 to 1:10, preferably from 1:1 to 1:8. This ratio can be reduced from 1:10 to 1:1 by addition of bases.
According to a preferred procedure, only the solvent is initially charged, and the hydrazine IV and the alkyl 3-alkoxyacrylate III are added simultaneously dropwise over a period of from 10 min to 10 h, preferably 1-4 h. The particular advantage of this parallel addition consists in the fact that this allows the pH of the reaction mixture to be kept constant at approximately 10, without addition of a base being required. The maintenance of this pH, in turn, is essential for the regioselectivity of the reaction. When a pH of 10, for example, is maintained, it is possible to obtain regioisomer ratios I:II of more than 300:1.
Moreover, it has been found to be favorable to reduce the temperature after a certain reaction time and to allow the reaction to go to completion at a correspondingly lower temperature.
Suitable solvents or diluents are, for example, water, aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, alcohols, such as methanol and ethanol, and also ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, and nitriles, such as acetonitrile and propionitrile. It is of course also possible to use mixtures of the abovementioned solvents.
Preferred solvents are, for example, water, alcohols, such as methanol and ethanol, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole, diethylene glycol dialkyl ethers and tetrahydrofuran, and mixtures of these.
The hydrazines IV can be employed both neat and in the form of their aqueous solutions, some of which are commercially available.
Step b):
The reaction of the alkyl 3-alkoxyacrylates III with hydrazines IV to give the 1-substituted 3-hydroxypyrazoles II is preferably carried out by initially charging the hydrazine IV in a suitable solvent and metering in the alkyl 3-alkoxyacrylate VIII at from xe2x88x9230xc2x0 C. to 100xc2x0 C., preferably at 10-40xc2x0 C., over a period of from 10 min to 10 h, preferably 1-4 h. During this addition, the pH is kept between 11 and 14, preferably at 12-13, in particular at 12, by addition of a base. By adjusting the pH to the last-mentioned values, it is possible to obtain the 1-substituted 3-hydroxypyrazoles II in high regioselectivity. Suitable bases are alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide and potassium hydroxide, and tertiary amines. Preferred bases are alkali metal and alkaline earth metal hydroxides. Suitable solvents are those mentioned in step a).
Step c):
The overall process according to the invention starts with alkyl vinyl ethers of the formula V which are initially reacted at from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from -10xc2x0 C. to 80xc2x0 C., in particular from 20xc2x0 C. to 60xc2x0 C., with an acyl chloride of the formula VIa, VIb or VIc, to give the corresponding acyl chloride of the formula VII.
The reaction can be carried out without using solvents or diluents if the reaction partners are liquid at the reaction temperature. However, it is also possible to carry out the reaction in an aprotic solvent or diluent.
Suitable solvents or diluents are, for example, aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, and also ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, and nitrites, such as acetonitrile and propionitrile. It is of course also possible to use mixtures of the abovementioned solvents.
Particularly preferably, the reaction is carried out in the absence of a solvent, or in aromatic hydrocarbons such as toluene as solvent.
The reaction partners V and VI are generally reacted with each other in a ratio of from 0.1:1 to 1:1 mol of V/VIa, VIb or VIc, preferably from 0.2:1 to 0.8:1 mol of V/VIa, VIb or VIc, in particular from 0.4:1 to 0.6:1 mol of V/VIa, VIb or VIc.
Since both the halides VI and the acyl chloride VII which is formed are unstable toward moisture, it is recommended to carry out the reaction under exclusion of water, preferably under an atmosphere of protective gas (nitrogen or another inert gas).
In the case of the reaction of V with VIb or VIc, it may be advantageous to accelerate the reaction by addition of catalytic amounts of a tertiary amine, such as triethylamine or pyridine.
Step d):
At 30-80xc2x0 C., the resulting acyl chloride VII eliminates hydrogen chloride (HC1), giving the corresponding 3-alkoxyacryloyl chloride VIII.
For this step of the reaction, it may be advantageous to remove the hydrogen chloride which is formed from the reaction volume, by applying slightly reduced pressure or by passing inert gas through the reaction mixture or the reaction vessel, thus removing the hydrogen chloride which is formed.
The excess chloride of the formula VIa, VIb or VIc can be recycled into the synthesis and has to be removed in any case for the isolation of the pure product of value. This also applies to any catalysts which may have been added.
The resulting crude 3-alkoxyacryloyl chlorides VIII can be isolated in pure form by distillation or rectification.
However, they can also be converted directly, without further purification, into the corresponding alkyl 3-alkoxyacrylates III.
Step e):
The acyl chlorides VIII are generally esterified by adding the alcohol IX dropwise to the acyl chloride VIII, at from xe2x88x9220 to 80xc2x0 C., preferably at 0-50xc2x0 C., over a period of 0.5-8 h, preferably 1-6 h, and purifying the resulting alkyl 3-alkoxyacrylate III by continuous or batchwise distillation or rectification.
However, it is also possible to carry out the reaction in an aprotic solvent or diluent. Suitable solvents or diluents are, for example, aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, and also ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, and nitriles, such as acetonitrile and propionitrile. It is of course also possible to use mixtures of the abovementioned solvents.
It is recommended to carry out the reaction in the presence of hydrogen chloride-binding reagents, such as, for example, pyridine. It is of course also possible to use the last-mentioned reagents as solvents.
With respect to the intended use of the 1-substituted 5- and/or 3-hydroxypyrazoles of the formulae I and II, the following radicals are suitable substituents:
R1 
C1-C4-alkyl, such as methyl, ethyl, n-propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl;
C1-C6-alkyl, such as C1-C4-alkyl as mentioned above, and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-thylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-3-methylpropyl;
in particular methyl, ethyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and 1,1-dimethylpropyl;
C2-C6-alkenyl, such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-4-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3 pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl,
in particular 1-methyl-2-propenyl, 1-methyl-2-butenyl, 1,1-dimethyl-2-propenyl and 1,1-dimethyl-2-butenyl;
C2-C6-alkynyl, such as propargyl, 2-butynyl, 3-butenyl [sic], 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2 propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl;
C3-C6-cycloalkyl, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
in particular cyclopropyl and cyclohexyl;
C1-C4-alkoxy, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy and 1,1-dimethylethoxy,
in particular C1-C3-alkoxy, such as methoxy, ethoxy, isopropoxy;
where these groups may be unsubstituted or substituted by one to five halogen atoms, such as fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine, C1-C4-alkoxy, phenoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or a cyclic ring system having 3-14 ring atoms, where the substituents are as defined below:
C1-C6-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl and 1,1-dimethylethoxycarbonyl, in particular methoxycarbonyl;
C1-C6-alkylthiocarbonyl, such as methylthiocarbonyl, ethylthiocarbonyl, n-propylthiocarbonyl, in particular methylthiocarbonyl;
C1-C4-haloalkyl: a C1-C4-alkyl radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i.e., for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl and nonafluorobutyl;
A cyclic ring system having 3-14 ring atoms means, for example, the following groups: C3-C14-cycloalkyl, C3-C14-cycloalkenyl, aromatic groups, such as phenyl, naphthyl, and their partially hydrogenated derivatives. The cyclic ring systems may furthermore represent heterocyclic ring systems in which one, two or three carbon atoms may be replaced by heteroatoms, such as, for example, O, N, S. In principle, the cyclic ring systems may be aromatic or partially or fully hydrogenated. The cyclic ring systems can be substituted at will. Suitable substituents are, for example, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, halogen, cyano, nitro, hydroxyl, thionyl, sulfoxyl, sulfonyl, C1-C4-alkylsulfonyl, amino, C1-C4-alkylamino and di-C1-C4-alkylamino.
Preference is given to cyclic ring systems from the group consisting of C1-C6-cycloalkyl, phenyl, a 5- to 6-membered heterocyclic, saturated or unsaturated radical containing one to three heteroatoms selected from the group consisting of O, N and S. each of which may be substituted as mentioned above.
Particular preference is given to C1-C6-cycloalkyl and phenyl which may be substituted as mentioned above.
A very particularly preferred cyclic ring system is phenyl which may be substituted as mentioned above.
R2, R3 independently of one another [lacuna] C1-C6-alkyl as mentioned above or C3-C6-cycloalkyl, preferably C1-C6-alkyl.